1. Field of the Invention
The present invention is directed to pharmaceutical compositions, and primarily to topically applied ophthalmic compositions comprising as the active ingredient one or more compounds having the ability to chelate calcium ions, e.g. intracellular calcium ions. The pharmaceutical compositions are useful for reducing intraocular pressure in animals of the mammalian species. In another aspect, the present invention is directed to administering such formulations and compositions to animals of the mammalian species (including humans) for reducing intraocular pressure in the eye.
2. Brief Description of the Prior Art
Glaucoma is an optical neuropathy associated with elevated intraocular pressures which are too high for normal function of the eye, and results in irreversible loss of visual function. It is estimated in medical science that glaucoma afflicts approximately 2 per cent of the population over the age of forty years, and is therefore a serious health problem. Ocular hypertension, i.e. the condition of elevated intraocular pressure, which has not yet caused irreversible damage, is believed to represent the earliest phase of glaucoma. Many therapeutic agents have been devised and discovered in the prior art for the treatment or amelioration of glaucoma and of the condition of increased intraocular pressure which precedes glaucoma. Other compounds known to be useful in treating intraocular pressure are disclosed in the following patents.
U.S. Pat. No. 3,467,756 describes anti-glaucoma and intraocular hypotensive compositions which contain in an ophthalmic vehicle 10, 11-dihydro-5-(3-methylaminopropyl)-5, 10-epoxy-11-hydroxy-5H-dibenzo a,d!cycloheptene or related derivatives.
U.S. Pat. No. 4,197,301 describes ophthalmic compositions which contain 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-(2-furanylcarbonyl)piperazine, also known under the name "prazosin".
U.S. Pat. No. 4,565,821 describes a method of topically administering certain dopamine antagonists to reduce ocular hypertension and to treat glaucoma.
U.S. Pat. No. 4,886,815 describes a method for treating retinal edema by administration of dopaminergic antagonists to a patient suffering from such conditions.
U.S. Pat. No. 5,066,664 describes 2-hydroxy-2-alkylphenylamino)-oxazolines and thiazolines as anti-glaucoma and vasoconstrictive agents.
U.S. Pat. No. 5,091,528 describe 6 or 7-(2-imino-2-imidazolidine)-1,4-benzoxazines as .alpha. adrenergic agents useful for treating glaucoma.
The foregoing and other anti-glaucoma and ocular hypotensive compounds and agents of the prior art do not provide such treatment or cure for glaucoma and ocular hypertension which is satisfactory in all respects. Therefore, the pharmacological and related arts and sciences continue searching for additional and better anti-glaucoma and ocular hypotensive agents.
1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) is a specific Ca.sup.2+ chelator that has been used to clamp extracellular Ca.sup.2+ to desired levels. On the other hand, the acetoxymethyl ester of BAPTA (BAPTA-AM) the uncharged esterified form of the parent compound is used to clamp intracellular Ca.sup.2+ (Ca.sup.2+ i). BAPTA-AM penetrates biological cell membranes and is hydrolyzed by intracellular esterases yielding the original charged impermeable form of the compound once again capable of buffering/clamping Ca.sup.2+. (This is reported in Molecular Probes: Handbook of Fluorescent Probes and Research Chemicals; Richard P. Haugland 1992-1994; Section 20: Calcium Indicators, Chelators and Ionophores, pages 119-128.)